Maternal cariprazine exposure inhibits embryonic and postnatal brain cholesterol biosynthesis

Abstract

Cariprazine (CAR) is a strong inhibitor of the Dhcr7 enzyme, the last enzyme in the cholesterol biosynthesis pathway. We assessed the effects of CAR on maternally exposed Dhcr7+/− and wild-type mouse offspring, and tested the biochemical effects of CAR in human serum samples. Dhcr7+/− and wild-type time-pregnant mice were exposed to vehicle or 0.2 mg/kg CAR from E12 to E19. Levels of CAR, CAR metabolites, sterols, and oxysterols were measured in the brain of maternally exposed offspring at various time points using LC-MS/MS. Embryonic exposure to CAR significantly increased levels of 7-DHC in all organs of exposed embryos, with a particularly strong effect in the brain. Detectable levels of CAR and elevated 7-DHC were observed in the brain of newborn pups 14 days after drug exposure. In addition, CAR altered sterol metabolism in all animals analyzed, with the strongest effect on the brain of Dhcr7+/− pups born to Dhcr7+/− dams. Furthermore, CAR elevated toxic oxysterols in the brain of maternally exposed Dhcr7+/− offspring to levels approaching those seen in a mouse model of Smith–Lemli–Opitz syndrome. Finally, we observed that patients taking CAR have elevated 7-DHC in their serum. In summary, maternal DHCR7 heterozygosity, combined with offspring DHCR7 heterozygosity might represent a vulnerability factor to medications that interfere with sterol biosynthesis. Due to the conserved sterol biosynthesis between mice and humans, we suggest that the 1–3% of patient population with single-allele DHCR7 mutations might not be ideal candidates for CAR use, especially if they are nursing, pregnant or plan to become pregnant.

Medication effects on developmental sterol biosynthesis

“…We used cultured mouse cortical neurons and astrocytes, Dchr7 +/− transgenic mouse models, and human dermal fibroblasts from individuals with single allele DHCR7 mutations (parents of children with SLOS) ( 51 ). Furthermore, we validated our findings in patients taking these medications ( 111 , 112 ).…”

“…This raised the question of whether genetic and environmental factors can interact, especially during development ( Figure 3 ). To test this, we assessed the roles of medication, maternal Dhcr7 genotype, offspring Dhcr7 genotype, and their interaction ( 110 , 111 ). Our work focused on three commonly prescribed medications: aripiprazole, trazodone and cariprazine.…”

“…We tested if medications given to pregnant mice affect cholesterol biosynthesis in developing brain of WT and Dhcr7 +/− embryos. Embryos were maternally exposed to aripiprazole, cariprazine, trazodone or vehicle from E12 to E19 ( 110 , 111 , 113 ). This exposure time was chosen based on developmental closure of blood-brain-barrier, and allowed us to examine endogenous brain sterol synthesis.…”

“…In summary, maternally administered aripiprazole, cariprazine and trazodone all inhibited DHCR7 activity, increased 7-DHC, elevated resulting oxysterols, and decreased desmosterol in the exposed pups’ brains. Due to its long half-life, detectable levels of CAR, and a corresponding elevation in 7-DHC levels were observed in the brain of newborn pups up to 14 days after drug exposure ( 111 ). Furthermore, three-way ANOVA analyses revealed that maternal Dhcr7 +/− genotype significantly contributed to the observed 7-DHC elevation for CAR and ARI, but the TRZ-driven changes appeared to be driven only by drug exposure and pup Dhcr7 +/− genotype.…”

Trazodone effects on developing brain

“…These properties were described initially in experiments with cell lines, followed by validation in animal models and human blood samples. Cariprazine 27 , 35 , haloperidol 20 , aripiprazole 36 , and TRZ are only a few examples of these DHCR7 inhibiting compounds. However, it should be noted that many other approved, non-CNS medications also show similar sterol-interfering effects, including amiodarone 28 .…”